(1) Field of Invention
The present invention is concerned with a novel economical process for the preparation of certain 5-halo-2-hydroxynicotinic acids by halogenation of 2-hydroxynicotinic acids with alkali-metal hypohalites in strongly alkaline solution. The reaction conditions and isolation procedures avoid substantial loss due to formation of 3,5-dihalo-2-hydroxypyridines caused by replacement of the carboxy group with a halogen atom.
(2) Information Disclosure Statement
Prior to the present invention, the halogenation of 2-hydroxynicotinic acids to produce 5-halo-2-hydoxynicotinic acids was not disclosed in the literature.
The chlorination of 2-hydroxypyridine has recently been disclosed by A. R. Katritsky et al. in the J. ORG. CHEM. (1984) 49: pp 4784-4786 but not prior to the present invention. In that disclosure 5-chloro-2-pyridine which is equivalent to 5-chloro-2-hydroxypyridine was prepared by reacting 1 equivalent of 2-pyridone (the same as 2-hydroxypyridine) with 10 equivalents of sodium hypochlorite. In contrast, the 2-hydroxypyridines of the present invention are substituted in the three position by a carboxy radical.
The preparation of 5-chloro-2-hydroxynicotinic acid from 5-amino-2-hydroxynicotinic acid, hydrochloric acid and sodium nitrate is described in U.S. Pat. Nos. 3,709,991 and 3,738,990.
H. M. Gilow in J. ORG. CHEM. (1974) vol. 39, 3481-3486 has reported on kinetics of bromination of some pyridinium ions such as 2,6-dimethylpyridinium to produce 3-bromo-2,6-dimethylpyridine using hypobromous acid in aqueous perchloric acid.
Chlorination of pyridinecarboxylic acids with thionyl chloride was discussed by E. Klingsberg in Chemistry of Heterocyclic Compound-Pyridine and Its Derivatives--Part Two page 308 (1961) published by Interscience Publishers, Inc. N.Y. and London. However, thionyl chloride would not be an appropriate chlorinating agent for 2-hydroxynicotinic acid enroute to 5-chloro-2-hydroxynicotinic acid inasmuch as it is known that hydroxyl groups are readily replaced with a chloro radical with this reagent. Klingsberg, ibid p. 307, states hydrogen chloride-hydrogen peroxide halogenation of hydroxypyridines is said to give good yields of isomer free products. Contrariwise in the instance of 2-hydroxynicotinic acid I found, as can be seen in my preliminary Trial B and C described hereinbelow, poor yields of the desired product and substantial loss occurred when hydrogen chloride and hydrogen peroxide were used due to replacement of the carboxy group with chlorine to give 3,5-dichloro-2-hydroxypyridine and other multiple halogen compounds.
The solid products of the process of this invention i.e., compounds of Formula I, are useful as hypolipidemics as described in U.S. Pat. Nos. 3,709,991 and 3,738,990. The compounds are also useful for the preparation of fused aromatic oxazepinones such as are described in U.S. Pat. No. 4,592,866 derived from application Ser. No. 746,091, filed June 18, 1985, which oxazepinones are useful as antihistaminics. Halogenation of 2-hydroxynicotinic acids using metal hypohalite was disclosed in the latter patent.
(3) Preliminary Experimental Trials
The following experimental trials A to G describe my early unsuccessful attempts to find an economical procedure for preparing 5-halo-2-hydroxynicotinic acid from 2-hydroxynicotinic acids.